Despite the rapid advances in elucidating the molecular basis of cancer, an ostensibly more difficult post-genomic challenge will be the functional annotation of Disease-specific signaling pathways. RNA interference makes possible for the first time, the use of large-scaile functional genomic strategies for target identification. The ultimate goal of the proposed project is to develop and establish a custom RNAi screening service based on functionally validated (FV) genome-wide human and mouse lentiviral shRNA libraries in arrayed and multiplex formates, and bioinformatics tools for analysis and use of this information in the drug discovery process. Phase I, Develop and screen a focused, FV shRNA collection to identify factors that are involved in the MCL-1 and p27kip1 signaling pathways. In addition to these proof-of-principle studies, proposed to validate and integrate genetic screening data with transcriptome profiling and molecular network information mined from scientific literature. The aforementioned genetic screening and bioinformatic strategies will provide the research community with hoghly modular, cost-effective approaches to understand and integrate the changes in these signal trasduction networks so that cnacer phenotypes can be delineated.